Parkinson's Disease

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"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- Parkinson's Disease -

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Observations:

In Parkinson's Disease, Brain Cells Abandon Mitochondria

ScienceDaily (Oct. 8, 2010) — In a study that sheds new light on the causes of Parkinson's disease, researchers report that brain cells in Parkinson's patients abandon their energy-producing machinery, the mitochondria. A shutdown in fuel can have devastating effects on brain cells, which consume roughly 20 percent of the body's energy despite making up only 2 percent of body weight... researchers, now show that a root cause of Parkinson's disease may lie in 10 gene sets related to energy production that spur neurons in the brain to "divorce" their mitochondria and related energy-producing pathways..."The most exciting result from our study for me is the discovery of PGC-1alpha as a new therapeutic target for early intervention in Parkinson's disease. PGC-1alpha is a master switch that activates hundreds of mitochondrial genes, including many of those needed to maintain and repair the power plants in the mitochondria,"... FDA-approved medications [Actos, CoQ10] that activate that PGC-1alpha are already available for widespread diseases like diabetes. These medications may jumpstart the development of new Parkinson's drugs; instead of having to start from scratch, pharmaceutical companies may be able to dust off their drug libraries and find look-alike drugs capable of targeting PGC-1alpha in the brain. "As we wrap up our first year of publishing the journal, the new study from Zheng et al. exemplifies the goal of Science Translational Medicine, applying knowledge and technology from different fields-such as neuroscience, genomics and bioinformatics-to achieve new discoveries,"...
http://www.sciencedaily.com/releases/2010/10/101006151557.htm

...A diabetes drug named Actos is among the compounds known to activate part of that PGC-1alpha pathway, and Weill Cornell's Beal says it's poised for an initial small trial in Parkinson's. Separately, a nutrient named Coenzyme Q10 is believed important in mitochondrial energy production, and Beal is leading a study to see if high doses might help Parkinson's. Results are due in 2012...

How The Pathology Of Parkinson's Disease Spreads
ScienceDaily (July 29, 2009) — Accumulation of the synaptic protein alpha-synuclein, resulting in the formation of aggregates called Lewy bodies in the brain, is a hallmark of Parkinson's and other related neurodegenerative diseases. This pathology appears to spread throughout the brain as the disease progresses. Now, researchers at the University of California, San Diego School of Medicine and Konkuk University in Seoul, South Korea, have described how this mechanism works... "The discovery of cell-to-cell transmission of this protein may explain how alpha-synuclein aggregates can pass to new, healthy cells," said first author Paula Desplats, project scientist in UC San Diego's Department of Neurosciences. "We demonstrated how alpha-synuclein is taken up by neighboring cells, including grafted neuronal precursor cells, a mechanism that may cause Lewy bodies to spread to different brain structures."... In these studies, autopsies of deceased Parkinson's patients who had received implants of therapeutic fetal neurons 11 to 16 years prior revealed that alpha-synuclein had propagated to the transplanted neurons...
http://www.sciencedaily.com/releases/2009/07/090727191914.htm]

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References:

--- Antioxidants for Parkinson's

Powerful Class of Antioxidants May Be Potent Parkinson's Treatment
ScienceDaily (July 23, 2012) — A new and powerful class of antioxidants could one day be a potent treatment for Parkinson's disease, researchers report.
A class of antioxidants called synthetic triterpenoids blocked development of Parkinson's in an animal model that develops the disease in a handful of days…
http://www.sciencedaily.com/releases/2012/07/120723134755.htm
http://news.georgiahealth.edu/archives/6054?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+ghsunews+%28GHSU+News%29

Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP- mouse model of Parkinson's disease.
Ammal Kaidery N, Banerjee R, Yang L, Smirnova NA, Hushpulian DM, Liby KT, Williams CW, Yamamoto M, Kensler TW, Ratan R, Sporn MB, Beal F, Gazaryan IG, Thomas B.
Antioxid Redox Signal. 2012 Jul 1. [Epub ahead of print]
Source: Georgia Health Sciences University, Pharmacology & Toxicology, Augusta, Georgia, United States;
Abstract
Although the etiology of Parkinson's disease (PD) remains unclear, ample empirical evidence suggest oxidative stress is a major player in the development of PD and in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-neurotoxicity. Nuclear factor E2-related factor 2 (Nrf2) is a redox sensitive transcription factor which upregulates a battery of antioxidant response element (ARE) driven antioxidative and cytoprotective genes that defend against oxidative stress. Aims: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids attenuate MPTP-induced PD in mice. Results: We show that synthetic triterpenoids are thus far the most potent and direct activators of the Nrf2 pathway using a novel Neh2-luciferase reporter. They upregulate several cytoprotective genes including those involved in glutathione biosynthesis in vitro. Oral administration of triterpenoids that were structurally modified to penetrate the brain induced mRNA and protein levels for a battery of Nrf2-dependent cytoprotective genes, reduced MPTP-induced oxidative stress and inflammation, and ameliorated dopaminergic neurotoxicity in mice. The neuroprotective effect of these triterpenoids against MPTP-neurotoxicity was dependent on Nrf2, since treatment with triterpenoids in Nrf2 knockout mice failed to block against MPTP-neurotoxicity and induce Nrf2-dependent cytoprotective genes. Innovation: Extremely potent synthetic triterpenoids that are direct activators of the Nrf2 pathway blocks dopaminergic neurodegeneration in the MPTP- mouse model of PD. Conclusion: Our results indicate that activation of Nrf2/ARE signaling by synthetic triterpenoids is directly associated with their neuroprotective effects against MPTP-neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD.
PMID: 22746536 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/22746536

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